Bacterial superantigens are a family of polypeptide exotoxins. Unlike conventional antigens, bacterial superantigens cause robust activation of a large proportion of CD4+ and CD8+ T cells based on their T cell receptor variable gene beta usage and not on their antigen specificities. Bacterial superantigens are implicated in a spectrum of diseases such as food poisoning, toxic shock syndromes, Kawasaki disease, asthma, atopic dermatitis and vasculitic and autoimmune disorders. Bacterial superantigens, especially staphylococcal enterotoxin B, may also be used as biological weapons. Superantigens are produced primarily by Staphylococcus aureus and Streptococcus pyogenes. The former can be present even in healthy individuals (particularly the nasal passage) called carriers. In spite of their immense clinical importance, there is a significant knowledge gap in our understanding of the immunobiology of bacterial superantigens. This is largely attributed to the dearth of suitable animal models that can recapitulate human diseases because bacterial superantigens fail to interact efficiently with non-human MHC class II molecules. Transgenic expression of human MHC class II molecules (which are the high affinity ligands for bacterial superantigens) in mice dramatically augments their immune response to bacterial superantigens and renders HLA class II transgenic mice susceptible to superantigen-mediated pathology including toxic shock. Availability of these convenient mouse models enables us to better understand the pathobiology of bacterial superantigens. We have developed numerous lines of HLA class II transgenic mice and introduced a number of genetic manipulations of immunological significance in these mice. Using these robust humanized mouse models, we plan to: (1) Delineate the pathogenesis of bacterial superantigen-induced acute clinical syndrome;(2) Dissect the role of components of the immune system in the pathogenesis of bacterial superantigen-induced acute clinical syndrome;and (3) Evaluate the role of staphylococcal superantigens in the etiopathogenesis of certain inflammatory disorders of respiratory system. Superantigens are bacterial toxins, which are extremely harmful to human beings;miniscule quantities are sufficient to cause severe disease. As superantigens fail to induce disease in commonly used experimental mice, we have developed new strains of mice expressing human molecules. These mice suffer from superantigen-induced disease like humans and can be effectively used to understand disease process associated with bacterial superantigens and to develop novel drugs and vaccines.